1. The Field of the Invention
The present invention generally relates to a polymer/drug-coated stent. More particularly, the polymer/drug-coated stent is configured have the drug disposed within the polymer coating in a manner that controls the elution of the drug so as to preferentially deliver the drug into vascular tissue adjacent to the stent while maintaining a sufficiently low systemic concentration range of the drug below a specified value.
2. The Relevant Technology
Endovascular techniques have become important adjuncts in the management of atherosclerotic occlusive disease. Once amendable only to open surgical revascularization, a wide range of lesions can now be approached percutaneously without the need for incision and dissection. Endovascular interventions within coronary arteries are particularly effective, and have become the preferred method of treatment for the majority of patients with occlusive syndromes of the coronary circulation.
Endovascular intervention in the peripheral circulation has proven more problematic. Although generally effective in the relatively large inflow arteries of the extracranial cerebrovascular, renal and iliac circulations, endovascular manipulation of the infrainguinal arteries is technically more challenging, and the outcome less durable.
A variety of approaches have been suggested to enhance patency during peripheral endovascular intervention including pharmacotherapy, stenting, cryoplasty, cutting balloon angioplasty, radiation brachytherapy and atherectomy. The most popular to date is stenting, as results from a recent randomized clinical trial suggest that routine nitinol stenting enhances both angiographic and clinical results following balloon angioplasty, especially in patients with long, complex occlusive lesions of the superficial femoral artery (SFA).
However, the long-term results of stenting in the peripheral vasculature continue to be plagued by restenosis. Restenosis, mediated by the pathological process of neointimal hyperplasia, complicates roughly 40% of all peripheral vascular interventions after one year, leading a recent international consensus panel of cardiologists, vascular surgeons, and interventional radiologists to suggest that the current state-of-the-art of SFA stenting results in only 62% patency after one year.
As significant enhancements in stented arterial patency have been achieved in the coronary circulation through the use of drug-eluting stents (DES), it was natural that this technology would be eventually applied to the peripheral circulation. Several small series have been published that suggest that drug-eluting stents designed for the coronary arteries might also be efficacious in limiting restenosis and improving patency in the infrapopliteal arteries. Similarly, the hypothesis that drug-eluting stents might also be efficacious in the larger and more complex SFA was previously addressed. Also, self-expanding drug-eluting stents utilized a nitinol platform, was loaded with 90 μg sirolimus/cm2 stent area using a 5-10 μm co-polymer matrix for total drug load ˜1 mg per 80 mm stent (i.e., stent 1), and delivered its drug load over a period of about seven days. A total of 93 patients were enrolled in combined clinical trials for the stent. Unfortunately, neither trial achieved its primary endpoint of a reduction in restenosis and, even after four years, there was no difference in any metric comparing patients treated with the bare nitinol stent vs. the sirolimus-eluting nitinol stent. The development of this drug-eluting stent was terminated, and no drug-eluting stent is yet available for clinical use anywhere in the world.
In retrospect, some have hypothesized that the failure of the drug-eluting stent design (e.g., stent 1) was in its inadequate drug delivery. As stated, Stent 1 was loaded with 90 μg sirolimus/cm2 stent area which was lower that one successful sirolimus-eluting coronary stent (e.g., stent 2), which had 140 μg sirolimus/cm2 stent area. Moreover, stent 1 released sirolimus over about seven days, which is considerably shorter than the 30 day release of stent 2, both being insufficient in duration for intended therapeutic purposes. As coronary stents with short elution profiles are generally less efficacious than their longer-eluting counterparts, it was perhaps not surprising that stent I failed to demonstrate efficacy in reducing restenosis.
A second observation made from the aforementioned studies was that large peripheral drug-eluting stents with relatively high drug loads and fast elution can subsequently generate significant levels of drug in the systemic circulation. These systemic levels of drug can be considered unsafe and may have adverse side effects. In any event, high systemic levels of drug is not advantageous and may counteract the intended therapy. Some coronary drug-eluting stents, with their minimal drug loads (−100 μg), generate little in the way of systemic drug concentration; whole blood levels exceeding 2 ng/ml are rarely observed. In contrast, large peripheral drug-eluting stents carry drug loads in the milligram (mg) range, and thereby have extremely fast drug elution that increases systemic concentration of the drug and may result in adverse systemic drug exposure. Such was the case in the aforementioned trial in which treated patients exhibited a mean systemic sirolimus concentration of 20.4±10.0 ng/ml one hour after stenting, including one patient with a peak concentration of 35.5 ng/ml sirolimus after receiving three 80 mm stents configured as stent 1. These concentrations are measurably higher than the 9 ng/ml trough concentration observed in kidney transplant recipients receiving the usual oral dose of sirolimus of 2 mg per day. These high systemic drug concentrations have been deemed excessive in terms of adverse effects that may occur by long-term exposure to high systemic drug concentrations.
Lastly, a final unexpected consequence of the aforementioned trial, and a possible reason for its failure, was the observation that the stent platform was prone to fracture. Of the 93 patients enrolled, stent fracture was found in 18% at six months, including single strut fractures in eight patients, multiple strut fractures in four patients, complete transverse linear stent separations in two patients, and transverse linear fractures with stent displacement in two patients. It has been suggested that stent fracture may create a nidus for restenosis, given the documented association between strut fracture, restenosis and therapeutic failure. Indeed, the reported frequency of strut fracture following peripheral stenting is surprisingly high, including one retrospective clinical study demonstrating a fracture rate of 65%.